Wednesday, 30 November 2016

Last night the cardboard 9 Hole Peg Test won “Innovation of the year” at the Barts Health Innovation Awards!

“This award is for an innovative idea that can be developed into a product (e.g. app, device, diagnostic test).”

We’re obviously not working in this area to win awards, but a little recognition now and again is no bad thing. The judges agreed that this is innovative as it is not only environmentally friendly and much cheaper than the plastic version, but innovative in how we are using it to raise awareness about the importance of upper limb function within the #ThinkHand campaign.

We’re in the process of setting up a distribution service so people can order their own test and we will let you know as soon as this is up and running.

I’d like to take this opportunity to say thank you to Biogen for funding the project, to Angelika Bauer and her team at ECTRIMS and MS Life and also The Agency of Design for their magnificent manufacturing skills.

The making of...

Lazer cutting 2000 test ready for distribution at ECTRIMS and MS Life in September.

BACKGROUND: Interferons-beta (IFNs-beta) and glatiramer acetate (GA) were the first two disease-modifying therapies (DMTs) approved 20 years ago for the treatment of multiple sclerosis (MS). DMTs' prescription rates as first or switching therapies and their costs have both increased substantially over the past decade. As more DMTs become available, the choice of a specific DMT should reflect the risk/benefit profile, as well as the impact on quality of life. As MS cohorts enrolled in different studies can vary significantly, head-to-head trials are considered the best approach for gaining objective reliable data when two different drugs are compared. The purpose of this systematic review is to summarise available evidence on the comparative effectiveness of IFNs-beta and GA on disease course through the analysis of head-to-head trials.This is an update of the Cochrane review 'Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis' (first published in the Cochrane Library 2014, Issue 7). OBJECTIVES:To assess whether IFNs-beta and GA differ in terms of safety and efficacy in the treatment of people with relapsing-remitting (RR) MS. SEARCH METHODS:We searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group (08 August 2016) and the reference lists of retrieved articles. We contacted authors and pharmaceutical companies. SELECTION CRITERIA:Randomised controlled trials (RCTs) comparing directly IFNs-beta versus GA in study participants affected by RRMS. DATA COLLECTION AND ANALYSIS:We used standard methodological procedures as expected by Cochrane. MAIN RESULTS:Six trials were included and five trials contributed to this review with data. A total of 2904 participants were randomly assigned to IFNs (1704) and GA (1200). The treatment duration was three years for one study, two years for the other four RCTs while one study was stopped early (after one year). The IFNs analysed in comparison with GA were IFN-beta 1b 250 mcg (two trials, 933 participants), IFN-beta 1a 44 mcg (three trials, 466 participants) and IFN-beta 1a 30 mcg (two trials, 305 participants). Enrolled participants were affected by active RRMS. All studies were at high risk for attrition bias. Three trials are still ongoing, one of them completed.Both therapies showed similar clinical efficacy at 24 months, given the primary outcome variables (number of participants with relapse (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.87 to 1.24) or progression (RR 1.11, 95% CI 0.91 to 1.35). However at 36 months, evidence from a single study suggests that relapse rates were higher in the group given IFNs than in the GA group (RR 1.40, 95% CI 1.13 to 1.74, P value 0.002).Secondary magnetic resonance imaging (MRI) outcomes analysis showed that effects on new or enlarging T2- or new contrast-enhancing T1 lesions at 24 months were similar (mean difference (MD) -0.15, 95% CI -0.68 to 0.39, and MD -0.14, 95% CI -0.30 to 0.02, respectively). However, the reduction in T2- and T1-weighted lesion volume was significantly greater in the groups given IFNs than in the GA groups (MD -0.58, 95% CI -0.99 to -0.18, P value 0.004, and MD -0.20, 95% CI -0.33 to -0.07, P value 0.003, respectively).The number of participants who dropped out of the study because of adverse events was similar in the two groups (RR 0.95, 95% CI 0.64 to 1.40).The quality of evidence for primary outcomes was judged as moderate for clinical end points, but for safety and some MRI outcomes (number of active T2 lesions), quality was judged as low. AUTHORS' CONCLUSIONS:The effects of IFNs-beta and GA in the treatment of people with RRMS, including clinical (e.g. people with relapse, risk to progression) and MRI (Gd-enhancing lesions) measures, seem to be similar or to show only small differences. When MRI lesion load accrual is considered, the effect of the two treatments differs, in that IFNs-beta were found to limit the increase in lesion burden as compared with GA. Evidence was insufficient for a comparison of the effects of the two treatments on patient-reported outcomes, such as quality-of-life measures.

As you may realise I am not a fan of these first line agents, simply because as this review indicates, for many they are not that good. However, some people respond to these agents and because of their relative safety compared to the more active drug there is some advantage. If only we had biomarkers on who responds to these drugs then their may be merit in them. Pharma has not done enough, but I guess they don't mind selling treatments to people who are not responding to themAlthough NDG says that the King and the Pawn go back into the same box, you don't mind dumping a few Pawns to save the king:-(

Should we reframe the CCSVI meme as a post-truth phenomenon? #ClinicSpeak #MSBlog #ResearchSpeak

After much discussion, debate, and research, the Oxford Dictionaries Word of the Year 2016 is post-truth – an adjective defined as ‘relating to or denoting circumstances in which objective facts are less influential in shaping public opinion than appeals to emotion and personal belief’.

The MS community has had its share of 'post-truisms'. The most recent that comes to mind is CCSVI. No matter how much the traditional 'MS establishment' or 'MS intelligentsia' spoke out against the concept of CCSVI the more a small, but very vocal, group that are now known as the CCSVIers were able to drown out the 'truth'.

Many years after the eye of the storm has passed the paper below comes out from the Canadian group showing that the prevalence of extracranial venous narrowing in pwMS is no different to that in siblings of pwMS and normal control subjects. It appears that these narrowings in the veins of pwMS are non-specific and therefore cannot be linked causally to MS. Will this be the last we hear of CCSVI? As a meme CCSVI, appears to have had its time in sun.

Purpose: The study sought to assess and compare the prevalence of narrowing of the major extracranial veins in subjects with multiple sclerosis and controls, and to assess the sensitivity and specificity of magnetic resonance venography (MRV) for describing extracranial venous narrowing as it applies to the chronic cerebrospinal venous insufficiency theory, using catheter venography (CV) as the gold standard.

Methods: The jugular and azygos veins were assessed with time-of-flight MRV in this assessor-blinded, case-control study of subjects with multiple sclerosis, their unaffected siblings, and unrelated controls. The veins were evaluated by diameter and area, and compared with CV. Collateral vessels were also analyzed for maximal diameter, as a potential indicator of compensatory flow.

Result: A high prevalence of extracranial venous narrowing was demonstrated in all study groups, collectively up to 84% by diameter criteria and 90% by area, with no significant difference between the groups when assessed independently (P = .34 and .63, respectively). There was high interobserver variability in the reporting of vessel narrowing (kappa = 0.32), and poor vessel per vessel correlation between narrowing on MRV and CV (kappa = 0.064). Collateral neck veins demonstrated no convincing difference in maximum size or correlation with jugular narrowing.

Conclusion: There is a high prevalence of narrowing of the major extracranial veins on MRV in all 3 study groups, with no significant difference between them. These findings do not support the chronic cerebrospinal venous insufficiency theory. Although MRV has shown a high sensitivity for identifying venous narrowing, time-of-flight imaging demonstrates poor interobserver agreement and poor specificity when compared with the gold standard CV.

Tuesday, 29 November 2016

Are you pro-PIRTs or would you prefer to be maintained? #ResearchSpeak #MSBlog #MSResearch

You may agree, or disagree, that one of the major advantages of the PIRTs (pulsed immune reconstitution therapies) is that they front-load risk with the potential to induce long-term remission and hopefully in some pwMS a potential cure. At present we only have one licensed PIRT, alemtuzumab. The study below confirms what we see clinically, that despite the burden or using alemtuzumab (cost, infusion reactions, secondary infections, monthly monitoring and secondary autoimmunity) pwMS have markedly improved quality of life (QoL) compared to pwMS on interferon-beta-1a.

It is quite remarkable how well pwMS feel post-alemtuzumab. I suspect having an inflammatory soup swishing around in your head, with active MS, makes you feel awful. Switching off inflammation and reducing the inflammatory mediators that drive so called 'sickness behaviour' clearly makes the difference. Sickness behaviour is the clinical syndrome associated with inflammation; i.e. fatigue, sleepiness, low mood, low energy, poor concentration, etc. If you don't have MS you may relate to how you feel when you have flu or a viral infection; you simply feel awful. From an evolutionary perspective sickness behaviour evolved to force the sick individual to rest and recover from illness. It is clear from this study, and my personal observations, that the interferons are not effective in abrogating sickness behaviour.

Another point that this study addresses is that the clinical effectiveness of alemtuzumab is mirrored by how pwMS feel and unction post-alemtuzumab. Please note improvements were noted in all QoL domains, i.e. physical, mental, and emotional. There are not many DMTs that do this.

Other PIRTS include cladribine, HSCT, mitoxantrone and possibly the anti-CD20 therapies. I suspect that a lot of clinicians will use ocrelizumab in a similar way to how some neurologists are currently using rituximab, i.e. with a 2-year course and then to retreat when disease activity re-emerges. Who knows we may even find a response marker that informs us about the need to retreat with anti-CD20? Now wouldn't the latter be disruptive?

METHODS: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36).

RESULTS: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS.

CONCLUSION: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

Cognitive dysfunction in patients with multiple sclerosis treated with first-line disease-modifying therapy: a multi-center, controlled study using the BICAMS battery.

Multiple sclerosis (MS) can impair cognitive functions even in the early stages. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery is very short and highly sensitive and can be used to evaluate cognitive status in the disease. Several clinical trials have shown beneficial effects of disease-modifying drugs (DMDs) on long-term cognitive measures which may even reduce cognitive deficits in MS patients. Relapsing remitting MS patients using DMDs were enrolled in the study and monitored for 12 months. BICAMS and the Expanded Disability Status Scale were applied to the study group. We evaluated and monitored 161 newly diagnosed cases of definite MS by the end of the trial. 110 patients (68.2%) were female. One hundred and two healthy subjects (female to male ratio 68:34) were enrolled into the study. MS patients were categorized into three DMT groups: IFNB1-a SC, IFNB1-b, and GA. Mean scores of all three cognitive tests (SDMT, BVMT-R, and CVLT-II) were significantly higher in the control group than in the MS patients. The number of cognitively impaired patients decreased from 31.7 to 21.7% on the basis of CVLT (p = 0.024), and 42 (26.1%) to 30 (18.6%) on the basis of BVMT-R at month 12. A significant difference was determined in terms of cognitive status between MS patients using both IFNB and GA and the healthy control group. Ours is the first study to compare IFNB and GA in terms of evaluating cognitive involvement and to use the BICAMS battery in monitoring treatment.

Figure: Comparison of percentages of cognitively impaired patients at baseline and at the end of study.

Realistically speaking, most neurologists have consigned the older 1st line injectables to the back of the sock drawer. This may be the effect of skilful marketing, but I believe on balance it is probably straight forward natural evolution. Like wrinkles on your face, MS treatments are also not resistant to the test of time. But can we give them an extra lease of life? This is what Cinar et al. propose, and use cognitive decline to make their case. Cognitive decline is a hidden threat in MS; very much overlooked in MS clinical trials, but vital to PwMS.

They studied 161 PwMS (on IFNb1a, IFNb1b, GA), with an average age of 30, disease duration of 2 years, and in education for 13 years. The mean SDMT (single digit modalities test) was 12.3 points higher in controls than in PwMS; even at this relatively young age and short duration of disease. The score, however, improved in all PwMS over the 12 months compared to baseline (see above figure), indicating that injectables have a beneficial impact on cognitive status. They did not find any difference between the three different treatments studied.

So it would appear that 1st line injectables still have some fight left in them. How would they then compare to the newer, and more highly active treatments, as far as cognition is concerned? Would they be better or simply the same? It is important to remember that at the end of the game, both the king and the pawn return to the same box.

Monday, 28 November 2016

Please hand me my rose-tinted glasses; I need to lend them to my colleagues. #ClinicSpeak #MSBlog #ECF2016I had a bit of a disagreement with several of my colleagues in Baveno. One didn't like the conclusion I drew about therapeutic lag and the effect of highly-active DMTs in so called 'non-relapsing progressive MS'. He was of the opinion that if we allowed people with progressive MS, who had no evidence of inflammatory activity on their MRIs, to be treated we would bankrupt the healthcare system. I pointed out to him that the majority of subjects in the natalizumab-SPMS, or ASCEND, trial had no MRI activity and they still responded to natalizumab. Similarly, both the MRI-active and MRI-inactive groups in the ocrelizumab in PPMS, or ORATORIO, trial responded to drug. What this is telling is that MRI is not the be-all and end-all of inflammatory monitoring. It is clear that there must still be inflammation going on beyond the detection threshold of the MRI; in fact, we have known this from pathology studies done more than 20 years ago. Another argument I had with him is that if we worry about costs and not the unmet need (progressive MS and loss of upper limb function) then we would be paralysed forever (excuse the pun). Pharmaceutical innovation costs are front loaded; in time the prices of drugs drop precipitously and become relatively cheap. When I was a house officer, and a medical registrar, there was a big debate about the high cost of statins and H2-receptor blockers; how could we as a society afford them? Fast forward 30 years and these drugs costs a few pence per day. The same will happen with DMTs in MS; trust me when I say that sometime in the future the cost of MS DMTs will be a fraction of what they cost today. Another factor to take into account is value-based pricing. In other words healthcare systems will work out how much to pay for DMTs in the more advanced stages of MS and they will negotiate a hard bargain with Pharma to reduce the costs. NICE does this already; what they do well is value-based pricing. Another argument I had was about my MS is 1-disease-not-2-or-3-diseases campaign. Several people disagreed. In the voting poll 48%, just shy of a majority, agreed with me. If I can get the community to accept this proposal then there should not be any resistance to treating MS as one disease. To get to this position you have to accept that MS is a modifiable disease even in the more advanced stages. I know what you are saying to yourself; 'Prof G must have written this post wearing his new rose-tinted spectacles'.

Sunday, 27 November 2016

IMPORTANCE:

With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.

OBJECTIVE:

To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).

DESIGN, SETTING, AND PARTICIPANTS:

Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).

MAIN OUTCOMES AND MEASURES:

NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.

RESULTS:

A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.

CONCLUSIONS AND RELEVANCE:

NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.

If you are interested in NEDA you can read this open access paper.

Do DMT cause NEDA in Relapsing MS, yes they can do and some are better than others. The best appears to be HSCT telling us that relapsing disease is driven by the actions of the immune system

Do the same DMT cause NEDA in progressive MS. I think the current view is that they probably do not do this at least quickly (using lower limb function as an out come) as evidenced with rituximab, alemtuzumab, caldribine and HSCT, because progressive MS appears to require a different approach to treatment (although some with say Singolimod), not to say that pwProgressive MS will not loose disease activity with such treatments as they do and that has been seen in trials (fingolimod & rituximab etc).

Counteracting the progressive neurological disability caused by neuronal and axonal loss is the major unmet clinical need in multiple sclerosis therapy. However, the mechanisms underlying irreversible neuroaxonal degeneration in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are not well understood. A long-standing hypothesis holds that the distribution of voltage-gated sodium channels along demyelinated axons contributes to neurodegeneration by increasing neuroaxonal sodium influx and energy demand during CNS inflammation. Here, we tested this hypothesis in vivo by inserting a human gain-of-function mutation in the mouse NaV1.2-encoding gene Scn2a that is known to increase NaV1.2-mediated persistent sodium currents. In mutant mice, CNS inflammation during EAE leads to elevated neuroaxonal degeneration and increased disability and lethality compared with wild-type littermate controls. Importantly, immune cell infiltrates were not different between mutant EAE mice and wild-type EAE mice. Thus, this study shows that increased neuronal NaV1.2 activity exacerbates inflammation-induced neurodegeneration irrespective of immune cell alterations and identifies NaV1.2 as a promising neuroprotective drug target in multiple sclerosis.

There are nine types of voltage dependent sodium channels. Nav1.6 is a common sodium channel at the node of ranvier which is were there is a gap between the myelin shealths. However during demyelination the sodium channels have to re-distribute along the new to maintain nerve conduction and Nav1.2 becomes expressed. In this study they expressed Nav1.2 into nerves and when there was the an inflammatory attact there was more damage from the inflammatory penumbra and this caused nerve damage.

Therefore sodium channel blockers show offer neuroprotection from the inflammatory penumbra and this is indeed what we showed during optic neuritis and are now attempting to do with PROXIMUS. This has recruited very slowly but we are attempting to determine if this approach works in MS and we are adding a nerve protecting sodium channel blocker on top of a DMT

Saturday, 26 November 2016

At last we begin to see treat-2-target of NEDA entering clinical practice. #NeuroSpeak #ClinicSpeak #MSBlogThe study below shows treating-2-target finaling getting traction in the real-world. Interestingly when you treat to target NEDA rates increase substantially. Why? One of the criticisms is that NEDA is very difficult to attain and several data sets have shown that NEDA rates are low. The reason why NEDA rates were low is because all these data were collected in an era when we weren't treating to a target; in other words people failing on a DMT, or with a suboptimal response, were left on their DMT. However, by treating to a target you are enriching for responders on a DMT and if someone is not responding you switch/escalate them to another DMT. By doing this you keep increasing the proportion of pwMS who are NEDA on a particular drug.The next development that has to enter the field is rebaselining. Not all people understand the need for rebaselining. This means that you exclude the period of time when the drug is not fully effective; with most DMTs this is first 3-6 months; the exceptions being glatiramer acetate (9 months) and PIRTS (pulsed immune reconstitution therapies) when you rebaseline after the treatment period, for example with alemtuzumab and cladribine this will be at 24 months.Surprise, surprise in the study below natalizumab and fingolimod or more effective at rendering pwMS NEDA than the injectables (interferon-beta and glatiramer acetate) and natalizumab has the edge over fingolimod. These hierarchy of efficacy is what you would expect from pivotal clinical trial results.

Prosperini et al. Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis.J Neurol. 2016 Nov 22. [Epub ahead of print]Background: In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis.Methods: As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively.Results: In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference.Conclusion: Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.CoI: multiple

It is clear that if you are a pwMS then personalised is based on your world view and the issues are 'quite soft'; e.g. listening skills, understanding, being treated as an equal, self-management, etc.. In comparison if you are a HCP then personalised is really about biology and choosing the most appropriate treatment, etc. I think we as HCPs should stick to the term precision medicine and leave the personalised medicine to people with disease, or the users of healthcare services. I will let you now how my talk goes or not; I am seriously outside of my comfort zone with this talk.

I have taken a lot of flak about rebranding MS a preventable dementia; why?

The study below clearly shows, and supports many other studies, that pwMS who have a high lesion load and reduced brain volume are more likely to be cognitively impaired. Are you surprised? Lesion volume (white dots) on MRI is an integrator of inflammation; the higher the lesion load the more inflammation you have had in the past. In comparison, brain volume is an integrator of end-organ damage and is a marker of how many neurons you have lost. Inflammation, the immunological shredder, damages and destroys nerves. This is why switching off inflammation in MS is strongly associated with a reduction in the rate of neuronal loss.

If I had MS I would not want to have any new lesions and I would want a normal sized brain that did not shrink faster than normal. The latter is what we are trying to promote as a treatment target; treat-2-target of NEDA.

It is time for pwMS to become activated and to ask their HCPs; do I have any ongoing inflammation on my MRI? If yes, you may want to push for a change in treatment. What about brain atrophy? How much end-organ damage have you acquired? The problem with that is that at present the measurement tools for brain volume change over time are not that reliable on an individual patient basis unless there is large amounts of atrophy. As I say this, I think this is a technological challenge and will be sorted out in the future. Another marker that may be better to measure is spinal fluid neurofilament levels; a marker of ongoing neuronal damage. The treatment aim is to normalise CSF neurofilament light levels, i.e. to prevent ongoing neuronal loss. If you love your brain you may just want to know about your spinal fluid neurofilament levels.

BACKGROUND AND PURPOSE: While impaired cognitive performance is common in multiple sclerosis (MS), it has been largely underdiagnosed. Here a magnetic resonance imaging (MRI) screening algorithm is proposed to identify patients at highest risk of cognitive impairment. The objective was to examine whether assessment of lesion burden together with whole brain atrophy on MRI improves our ability to identify cognitively impaired MS patients.

METHODS: Of the 1253 patients enrolled in the study, 1052 patients with all cognitive, volumetric MRI and clinical data available were included in the analysis. Brain MRI and neuropsychological assessment with the Brief International Cognitive Assessment for Multiple Sclerosis were performed. Multivariable logistic regression and individual prediction analysis were used to investigate the associations between MRI markers and cognitive impairment. The results of the primary analysis were validated at two subsequent time points (months 12 and 24).

Thursday, 24 November 2016

Immunosuppression as a treatment for multiple sclerosis. #NeuroSpeak #MSBlog #ECF2016As promised, my presentation from the opening Excemed medical education satellite symposium this morning at the European Charcot Foundation meeting in Baveno. I followed an excellent talk by Professor Reinhold Hohlfeld on the reshaping the immune system as a treatment strategy for MS. He used myeloablative HSCT as the example underpinning his talk. In comparison, my talk covered the treatment strategies that are currently being used in MS. I focused on the immunosuppressive agents, highligting the differences between maintaince and pulsed immunosuppression. I got very good feedback from the talk with several delegates requesting my slides.

Wednesday, 23 November 2016

Are you a fingolimoder? Are you aware about its opportunistic infection risk? #ClinicSpeak #Neurospeak #MSBlogI have been giving a series of talks about immunosuppression in MS and discuss the pros and cons of the different DMTs. I start off by defining what is an immunosuppressant and then discuss the different strategies for using these agents. There is a big difference between maintenance immunosuppression in which the drug is on-board all the time and the risk of opportunistic infections increases with time; i.e. the cumulative incidence increases with time and so does the risk. In comparison induction therapies, or as I prefer to call them PIRTS (pulsed immune reconstitution therapies) the risk is front-loaded and once the immune system reconstitutes the risk associated with immunosuppression drops massively. The case below of systemic cryptococcal infection and meningitis, an opportunistic fungal infection, in a pwMS on fingolimod is one of many cases reported worldwide. The problem with fingolimod is that you can't derisk the risk of opportunistic infections. All cases of opportunistic infection on fingolimod, to the best of my knowledge, have occurred in pwMS with lymphocyte counts above 200/mm3 or 0.2x109/L (the action level ti disruot dosing in the EU). In addition, infections in pwMS on fingolimod are not linked to the peripheral lymphocyte counts. Therefore, the only way to deal with the opportunistic infection risk on fingolimod is to remain vigilant and be aware of symptoms suggsetive of an infection. In the case of cryptococcal meningitis this may be very subtle symptoms; for example a non-specific headache or visual symptoms. The reason why cryptococcal infection is very indolent is simply because people who are immunosuppressed are unable to mount a vigorous immune response against the fungal agent concerned and hence don't present with symptoms of acute meningitis.

We herein report the case of a 63-year-old man who presented with a 3-month history of a cutaneous nodular lesion of his jaw, low grade fever, lethargy and progressive cognitive impairment. He had a 30-year history of multiple sclerosis and had been treated with fingolimod for the previous 2 years. Laboratory data revealed CD4 lymphocytopenia and a tissue culture of the skin nodule was positive for Cryptococcus neoformans. Cerebrospinal fluid and serum cryptococcal antigen tests were also positive and we diagnosed him to have disseminated cryptococcosis. This dissemination might be associated with fingolimod-induced CD4 lymphocytopenia. The risk of an opportunistic infection should therefore be considered when encountering fingolimod-treated patients.CoI: multiple

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